Diabetes mellitus is characterised by hyperglucagonemia and the failure or loss of the insulin producing beta cells in the pancreas. A way to cure diabetes is therefore to regenerate the functional beta cell mass and/or inhibit glucagon secretion from the alpha cell. Using genetically engineered mouse models, it has been demonstrated that alpha cells can be re-programmed into functional beta cells. Furthermore, the strategy has shown that mice are able to recover several times from a near complete ablation of beta cell mass. This re-programming depends on the interplay between the two transcription factors Arx and Pax4. During development, these were shown to display antagonistic activities in the processes underlying the specification of the endocrine subtype destinies through an inhibitory cross-regulatory circuit that controls the transcriptional state of these two genes (Al-Hasani et al., 2013).
In addition, several studies have demonstrated that GABA participates in maintaining beta-cell mass, by inducing beta-cell proliferation and protecting beta-cells from apoptosis in vitro. It was shown that GABA could decrease blood glucose levels and exert protective and regenerative effects on the beta-cell mass in streptozotocin-induced diabetes in mice. GABA was also found to reverse diabetes in NOD mice (Soltani et al., 2011) and induce proliferation in human islets (Purwana et al., 2014). The suggested explanation was that GABA might act in an autocrine/paracrine manner to regenerate the pancreatic islets via beta-cell proliferation. As described in the patent application WO2014048788 (P. Collombat) 16.09.2013, mice dosed with GABA are able to replenish the beta cell mass by neogenesis and conversion of alpha cells into beta cells.
The absence of glucagon signalling will lead to increased alpha cell mass. This self-renewal process has been shown in several transgenic mouse models: 1) the prohormone convertase-2 knock-out (PC2-KO) that cannot process proglucagon to glucagon (Furuta et al., 1997) and 2) the glucagon-receptor KO (that cannot sense glucagon) both leading to profound alpha-cell hyperplasia (Gelling et al., 2003). Similarly the proglucagon-KO mouse has a vast upregulation of glucagon-negative alpha cells in the islet of Langerhans which express Arx (Hayashi et al., 2009). Moreover, it has been shown that the liver-specific KO of the glucagon receptor has a similar alpha-cell hyperplasia compared to the global glucagon-receptor-KO suggesting the existence of liver derived factors mediating the alpha cell hyperplasia. It has also been shown that alpha cell hyperplasia can be induced in wild type animals. In rabbits immunized with glucagon over 9 months, one notes a dramatic expansion of the alpha cell mass.
Therefore, there is a need for an accelerated mechanism of inducible regeneration of alpha cells with the subsequent conversion into beta cells and reduction of hyperglucagonemia, for optimal therapeutic effect in diabetes patients.